Functional magnetic resonance imaging investigation of brain-wide activities and networks

Abstract

The brain is an extraordinary biological information processing system, consisting of numerous neuronal populations that are connected into functionally specialized circuits and networks. During active task or resting, brain coordinates various neural activities at different spatiotemporal scales across local circuits and/or brain-wide networks to execute functions, from which specific spatiotemporal patterns of brain activities and functional connectivity of brain regions arise. At present, little is known about the causal role(s) of transiently initiated neural oscillatory activities at key gates of brain-wide networks (e.g. thalamus for thalamo-cortico-thalamic network) in establishing brain-wide spatiotemporal patterns and facilitating brain-wide functional connectivity. Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a non-invasive technique that can monitor both evoked and spontaneous brain-wide activities through neurovascular coupling with high spatiotemporal resolution. This thesis aimed to develop and apply state-of-the-art neuromodulation and fMRI methods for in vivo investigation of brain-wide spatiotemporal patterns causally triggered by locally initiated neural activities and their contributions to brain-wide functional connectivity. A multi-modal approach of resting–state fMRI (rsfMRI), optogenetic stimulation, and multi-depth cortical electrophysiology recording was deployed to examine the contributions of thalamically initiated slow neural activity in brain-wide rsfMRI connectivity. Interhemispheric rsfMRI connectivity in all examined sensory cortices, somatosensory, visual and auditory, and the local intrahemispheric infraslow (0.01-0.1 Hz) BOLD activity were significantly enhanced after evoking robust brain-wide activations across these regions by low frequency (1Hz) optogenetic stimulation of somatosensory-specific ventral posteromedial (VPM) thalamocortical excitatory neurons. In parallel, multi-depth local field potential (LFP) recordings at bilateral primary somatosensory cortices revealed increased interhemispheric correlations of low frequency neural oscillations (i.e., mainly < 10 Hz) at all cortical layers. Meanwhile, pharmacologically inhibiting VPM thalamocortical neurons decreased interhemispheric rsfMRI connectivity and local intrahemispheric infraslow BOLD activity in all sensory cortices. These results demonstrate that locally initiated low frequency activities in the thalamo-cortical network contribute to brain-wide rsfMRI connectivity. Furthermore, these findings highlight the thalamus as a pivotal region that mediates brain-wide rsfMRI connectivity through recruiting polysynaptic connections and low frequency neural oscillations. The brain-wide activities triggered by locally initiated thalamo-cortical spindle-like activities and its role(s) in brain-wide rsfMRI connectivity were then explored through combined fMRI/rsfMRI and optogenetic stimulation. Specific and robust BOLD fMRI activations across brain-wide regions, including sensorimotor-related thalamo-cortical and midbrain regions, limbic system, and basal ganglia, were detected upon optogenetic stimulation of VPM at the typical temporal-frequency range of spontaneous spindles (i.e., < 3s and 8-14 Hz). Together with this brain-wide activation pattern, subsequent extracellular recording validated that the evoked spindle-like activity mimicked spontaneous thalamo-cortical spindles in multiple spatiotemporal characteristics (e.g. envelop, slow oscillation-spindle coupling, and layer-specific recurrent activities). Moreover, brain-wide interhemispheric rsfMRI connectivity in somatosensory cortices, motor cortex and limbic system, and inter-regional rsfMRI connectivity between cingulate and retrosplenial cortices were enhanced after the brain-wide spindle-related BOLD activations. These results establish the causal relationships between thalamo-cortically initiated spindle-like activities and specific brain-wide BOLD activation patterns as well as altered brain-wide rsfMRI connectivity. Future studies will combine similar approaches with task-based/behavior experiments to provide further understandings of brain-wide activities and networks.